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COVID-19 shares the feature of autoantibody production with systemic autoimmune diseases. In order to understand the role of these immune globulins in the pathogenesis of the disease, it is important to explore the autoantibody spectra. Here we show, by a cross-sectional study of 246 individuals, that autoantibodies targeting G protein-coupled receptors (GPCR) and RAS-related molecules associate with the clinical severity of COVID-19. Patients with moderate and severe disease are characterized by higher autoantibody levels than healthy controls and those with mild COVID-19 disease. Among the anti-GPCR autoantibodies, machine learning classification identifies the chemokine receptor CXCR3 and the RAS-related molecule AGTR1 as targets for antibodies with the strongest association to disease severity. Besides antibody levels, autoantibody network signatures are also changing in patients with intermediate or high disease severity. Although our current and previous studies identify anti-GPCR antibodies as natural components of human biology, their production is deregulated in COVID-19 and their level and pattern alterations might predict COVID-19 disease severity., (© 2022. The Author(s).)

The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial, involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response. Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19 from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the management of COVID-19., (© 2022. The Author(s).)

Introduction: As several clinical trials have revealed that angiotensin-converting enzyme inhibitors and angiotensin II (Ang II) receptor blockers may be efficient in treating vascular dementia (VaD), the long-acting blockade of the renin-angiotensin system (RAS) would be useful considering the poor adherence of antihypertensive drugs. Accordingly, we continuously blocked RAS via vaccination and examined the effectiveness of the VaD model in rats., Methods: Male Wistar rats were exposed to two-vessel occlusions (2VO) after three injections of Ang II peptide vaccine. The effects of the vaccine were evaluated in the novel object recognition test, brain RAS components, and markers for oligodendrocytes., Results: In the vaccinated rats, anti-Ang II antibody titer level was increased in serum until Day 168, but not in cerebral parenchyma. Vaccinated rats showed better object recognition memory with inhibited demyelination in the corpus callosum and activation of astrocytes and microglia. Also, levels of BrdU/GSTπ-positive cells and the phosphorylation of cAMP response element binding protein was increased in vaccinated rats, indicating that the differentiation of oligodendrocyte progenitor cells to mature oligodendrocytes was accelerated. Vaccinated rats showed increased expression of fibroblast growth factor-2 (FGF2), which was observed in endothelial cells. Angiotensinogen mRNA was decreased at 7 days after 2VO but increased at 14 and 28 days., Conclusion: Ang II vaccine might have promoted oligodendrocyte differentiation and inhibited astrocytic and microglial activation by stimulating FGF2 signaling in the endothelial cells-oligodendrocyte/astrocyte/microglia coupling. These data indicate the feasibility of Ang II vaccine for preventing progression of vascular dementia., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Cancer stem cells (CSCs) drive metastasis, treatment resistance, and tumor recurrence. CSCs reside within a niche , an anatomically distinct site within the tumor microenvironment (TME) that consists of malignant and non-malignant cells, including immune cells. The renin-angiotensin system (RAS), a critical regulator of stem cells and key developmental processes, plays a vital role in the TME. Non-malignant cells within the CSC niche and stem cell signaling pathways such as the Wnt, Hedgehog, and Notch pathways influence CSCs. Components of the RAS and cathepsins B and D that constitute bypass loops of the RAS are expressed on CSCs in many cancer types. There is extensive in vitro and in vivo evidence showing that RAS inhibition reduces tumor growth, cell proliferation, invasion, and metastasis. However, there is inconsistent epidemiological data on the effect of RAS inhibitors on cancer incidence and survival outcomes, attributed to different patient characteristics and methodologies used between studies. Further mechanistic studies are warranted to investigate the precise effects of the RAS on CSCs directly and/or the CSC niche . Targeting the RAS, its bypass loops, and convergent signaling pathways participating in the TME and other key stem cell pathways that regulate CSCs may be a novel approach to cancer treatment.

Background: Activation of the immune system is implicated in the Post-Acute Sequelae after SARS-CoV-2 infection (PASC) but the mechanisms remain unknown. Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin II (Ang II) resulting in decreased activation of the AT1 receptor and decreased immune system activation. We hypothesized that autoantibodies against ACE2 may develop after SARS-CoV-2 infection, as anti-idiotypic antibodies to anti-spike protein antibodies., Methods and Findings: We tested plasma or serum for ACE2 antibodies in 67 patients with known SARS-CoV-2 infection and 13 with no history of infection. None of the 13 patients without history of SARS-CoV-2 infection and 1 of the 20 outpatients that had a positive PCR test for SARS-CoV-2 had levels of ACE2 antibodies above the cutoff threshold. In contrast, 26/32 (81%) in the convalescent group and 14/15 (93%) of patients acutely hospitalized had detectable ACE2 antibodies. Plasma from patients with antibodies against ACE2 had less soluble ACE2 activity in plasma but similar amounts of ACE2 protein compared to patients without ACE2 antibodies. We measured the capacity of the samples to inhibit ACE2 enzyme activity. Addition of plasma from patients with ACE2 antibodies led to decreased activity of an exogenous preparation of ACE2 compared to patients that did not have antibodies., Conclusions: Many patients with a history of SARS-CoV-2 infection have antibodies specific for ACE2. Patients with ACE2 antibodies have lower activity of soluble ACE2 in plasma. Plasma from these patients also inhibits exogenous ACE2 activity. These findings are consistent with the hypothesis that ACE2 antibodies develop after SARS-CoV-2 infection and decrease ACE2 activity. This could lead to an increase in the abundance of Ang II, which causes a proinflammatory state that triggers symptoms of PASC., Competing Interests: The authors have declared that no competing interests exist.

The objective of this work was to study the effects and mechanisms of S-allylmercapto-N-acetylcysteine (ASSNAC) in the treatment of pulmonary emphysema based on network pharmacology analysis and other techniques. Firstly, the potential targets associated with ASSNAC and COPD were integrated using public databases. Then, a protein-protein interaction network was constructed using String database and Cytoscape software. The Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were performed on DAVID platform. The molecular docking of ASSNAC with some key disease targets was implemented on the SwissDock platform. To verify the results of the network pharmacology, a pulmonary emphysema mice model was established and treated with ASSNAC. Besides, the expressions of the predicted targets were detected by immunohistochemistry, Western blot analysis or enzyme-linked immunosorbent assay. Results showed that 33 overlapping targets are achieved, including CXCL8, ICAM1, MAP2K1, PTGS2, ACE and so on. The critical pathways of ASSNAC against COPD involved arachidonic acid metabolism, chemokine pathway, MAPK pathway, renin-angiotensin system, and others. Pharmacodynamic experiments demonstrated that ASSNAC decreased the pulmonary emphysema and inflammation in the pulmonary emphysema mice. Therefore, these results confirm the perspective of network pharmacology in the target verification, and indicate the treatment potential of ASSNAC against COPD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Since the discovery of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), numerous research has been undertaken to delineate the various effects of the virus which manifests in many ways all over the body. The association between the SARS-CoV-2 invasion mechanism and the renin-angiotensin-aldosterone system (RAAS) receptors, created many debates about the possible consequences of using RAAS-modulating drugs including angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) during the pandemic. Many clinical studies were conducted to assess the outcomes of coronavirus disease 2019 (COVID-19) in patients who use ACEi/ARBs following the arguments claiming to discontinue these drugs as a precautionary measure. Although several studies mainly analyzed the outcomes of the disease, this review aimed to compare specific blood markers in both groups of COVID-19 patients to gain better insight into the interaction of ACEi/ARBs with different body functions during the infection. Several databases were searched using a combination of keywords followed by screening and data extraction. Only 28 studies met our inclusion criteria, the majority of which showed no significant difference between the inflammation markers of COVID-19 patients who used or did not use ACEi/ARBs. Interestingly, 6 studies reported lower inflammatory markers in COVID-19 patients who used ACEi/ARBs, and 6 studies reported better outcomes among the same group. We therefore concluded that the use of ACEi/ARBs may not lead to worse prognosis of COVID-19 and may even play a protective role against the hyperinflammatory response associated with COVID-19., (© 2021, The American College of Clinical Pharmacology.)

The renin-angiotensin system (RAS) plays a major role in COVID-19. Severity of several inflammation-related diseases has been associated with autoantibodies against RAS, particularly agonistic autoantibodies for angiotensin type-1 receptors (AA-AT1) and autoantibodies against ACE2 (AA-ACE2). Disease severity of COVID-19 patients was defined as mild, moderate or severe following the WHO Clinical Progression Scale and determined at medical discharge. Serum AA-AT1 and AA-ACE2 were measured in COVID-19 patients (n = 119) and non-infected controls (n = 23) using specific solid-phase, sandwich enzyme-linked immunosorbent assays. Serum LIGHT (TNFSF14; tumor necrosis factor ligand superfamily member 14) levels were measured with the corresponding assay kit. At diagnosis, AA-AT1 and AA-ACE2 levels were significantly higher in the COVID-19 group relative to controls, and we observed significant association between disease outcome and serum AA-AT1 and AA-ACE2 levels. Mild disease patients had significantly lower levels of AA-AT1 (p < 0.01) and AA-ACE2 (p < 0.001) than moderate and severe patients. No significant differences were detected between males and females. The increase in autoantibodies was not related to comorbidities potentially affecting COVID-19 severity. There was significant positive correlation between serum levels of AA-AT1 and LIGHT (TNFSF14; r Pearson  = 0.70, p < 0.001). Both AA-AT1 (by agonistic stimulation of AT1 receptors) and AA-ACE2 (by reducing conversion of Angiotensin II into Angiotensin 1-7) may lead to increase in AT1 receptor activity, enhance proinflammatory responses and severity of COVID-19 outcome. Patients with high levels of autoantibodies require more cautious control after diagnosis. Additionally, the results encourage further studies on the possible protective treatment with AT1 receptor blockers in COVID-19., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The renin-angiotensin system (RAS) has long been described in the field of cardiovascular physiology as the main player in blood pressure homeostasis. However, other effects have since been described, and include proliferation, fibrosis, and inflammation. To illustrate the immunomodulatory properties of the RAS, we chose three distinct fields in which RAS may play a critical role and be the subject of specific treatments. In oncology, RAS hyperactivation has been associated with tumor migration, survival, cell proliferation, and angiogenesis; preliminary data showed promise of the benefit of RAS blockers in patients treated for certain types of cancer. In intensive care medicine, vasoplegic shock has been associated with severe macro- and microcirculatory imbalance. A relative insufficiency in angiotensin II (AngII) was associated to lethal outcomes and synthetic AngII has been suggested as a specific treatment in these cases. Finally, in solid organ transplantation, both AngI and AngII have been associated with increased rejection events, with a regional specificity in the RAS activity. These elements emphasize the complexity of the direct and indirect interactions of RAS with immunomodulatory pathways and warrant further research in the field.

More than one year since its emergence, corona virus disease 2019 (COVID-19) is still looming large with a paucity of treatment options. To add to this burden, a sizeable subset of patients who have recovered from acute COVID-19 infection have reported lingering symptoms, leading to significant disability and impairment of their daily life activities. These patients are considered to suffer from what has been termed as "chronic" or "long" COVID-19 or a form of post-acute sequelae of COVID-19, and patients experiencing this syndrome have been termed COVID-19 long-haulers. Despite recovery from infection, the persistence of atypical chronic symptoms, including extreme fatigue, shortness of breath, joint pains, brain fogs, anxiety and depression, that could last for months implies an underlying disease pathology that persist beyond the acute presentation of the disease. As opposed to the direct effects of the virus itself, the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is believed to be largely responsible for the appearance of these lasting symptoms, possibly through facilitating an ongoing inflammatory process. In this review, we hypothesize potential immunological mechanisms underlying these persistent and prolonged effects, and describe the multi-organ long-term manifestations of COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ramakrishnan, Kashour, Hamid, Halwani and Tleyjeh.)

The severe acute respiratory syndrome coronavirus (SARS-CoV)-2, which is responsible for coronavirus disease 2019 (COVID-19), uses angiotensin (ANG)-converting enzyme 2 (ACE2) as the entrance receptor. Although most COVID-19 cases are mild, some are severe or critical, predominantly due to acute lung injury. It has been widely accepted that a counter regulatory renin-angiotensin system (RAS) axis including the ACE2/ANG [1-7]/Mas protects the lungs from acute lung injury. However, recent evidence suggests that the generation of protective ANG [1-7] in the lungs is predominantly mediated by proinflammatory prolyl oligopeptidase (POP), which has been repeatedly demonstrated to be involved in lung pathology. This review contends that acute lung injury in severe COVID-19 is characterised by a) ACE2 downregulation and malfunction (inflammatory signalling) due to viral occupation, and b) dysregulation of the protective RAS axis, predominantly due to increased activity of proinflammatory POP. It follows that a reasonable treatment strategy in COVID-19-related acute lung injury would be delivering functional recombinant (r) ACE2 forms to trap the virus. Additionally, or alternatively to rACE2 delivery, the potential benefits resulting from lowering POP activity should also be explored. These treatment strategies deserve further investigation., (Copyright © 2020 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

The most classical view of the renin-angiotensin system (RAS) emphasizes its role as an endocrine regulator of sodium balance and blood pressure. However, it has long become clear that the RAS has pleiotropic actions that contribute to organ damage, including modulation of inflammation. Angiotensin II (Ang II) activates angiotensin type 1 receptors (AT1R) to promote an inflammatory response and organ damage. This represents the pathophysiological basis for the successful use of RAS blockers to prevent and treat kidney and heart disease. However, other RAS components could have a built-in capacity to brake proinflammatory responses. Angiotensin type 2 receptor (AT2R) activation can oppose AT1R actions, such as vasodilatation, but its involvement in modulation of inflammation has not been conclusively proven. Angiotensin-converting enzyme 2 (ACE2) can process Ang II to generate angiotensin-(1-7) (Ang-(1-7)), that activates the Mas receptor to exert predominantly anti-inflammatory responses depending on the context. We now review recent advances in the understanding of the interaction of the RAS with inflammation. Specific topics in which novel information became available recently include intracellular angiotensin receptors; AT1R posttranslational modifications by tissue transglutaminase (TG2) and anti-AT1R autoimmunity; RAS modulation of lymphoid vessels and T lymphocyte responses, especially of Th17 and Treg responses; interactions with toll-like receptors (TLRs), programmed necrosis, and regulation of epigenetic modulators (e.g. microRNAs and bromodomain and extraterminal domain (BET) proteins). We additionally discuss an often overlooked effect of the RAS on inflammation which is the downregulation of anti-inflammatory factors such as klotho, peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), transient receptor potential ankyrin 1 (TRPA1), SNF-related serine/threonine-protein kinase (SNRK), serine/threonine-protein phosphatase 6 catalytic subunit (Ppp6C) and n-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). Both transcription factors, such as nuclear factor κB (NF-κB), and epigenetic regulators, such as miRNAs are involved in downmodulation of anti-inflammatory responses. A detailed analysis of pathways and targets for downmodulation of anti-inflammatory responses constitutes a novel frontier in RAS research., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The renin-angiotensin-aldosterone system and its metabolites play an important role in homeostasis of body, especially the cardiovascular system. In this study, we discuss the imbalance of multiple systems during the infection and the importance of therapeutic choice, dosing, and laboratory monitoring of cardiac and anti-coagulant therapies in COVID-19 patients. The crosstalk between angiotensin, kinin-kallikrein system, as well as inflammatory and coagulation systems plays an essential role in COVID-19. Cardiac complications and coagulopathies imply the crosstalks between the mentioned systems. We believe that the blockage of bradykinin can be a good option in the management of COVID-19 and CVD in patients and that supportive treatment of respiratory and cardiologic complications is needed in COVID-19 patients. Ninety-one percent of COVID-19 patients who were admitted to hospital with a prolonged aPTT were positive for lupus anticoagulant, which increases the risk of thrombosis and prolonged aPTT. Therefore, the question that is posed at this juncture is whether it is safe to use the prophylactic dose of heparin particularly in those with elevated D-dimer levels. It should be noted that timing is of high importance in anti-coagulant therapy; therefore, we should consider the level of D-dimer, fibrinogen, drug-drug interactions, and risk factors during thromboprophylaxis administration. Fibrinogen is an independent predictor of resistance to heparin and should be considered before thromboprophylaxis. Alteplase and Futhan might be a good choice to assess the condition of heparin resistance. Finally, the treatment option, dosing, and laboratory monitoring of anticoagulant therapy are critical decisions in COVID-19 patients.

Since the outbreak of coronavirus disease 2019 (COVID-19) in 2019, it is gaining worldwide attention at the moment. Apart from respiratory manifestations, neurological dysfunction in COVID-19 patients, especially the occurrence of cerebrovascular diseases (CVD), has been intensively investigated. In this review, the effects of COVID-19 infection on CVD were summarized as follows: (I) angiotensin-converting enzyme 2 (ACE2) may be involved in the attack on vascular endothelial cells by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), leading to endothelial damage and increased subintimal inflammation, which are followed by hemorrhage or thrombosis; (II) SARS-CoV-2 could alter the expression/activity of ACE2, consequently resulting in the disruption of renin-angiotensin system which is associated with the occurrence and progression of atherosclerosis; (III) upregulation of neutrophil extracellular traps has been detected in COVID-19 patients, which is closely associated with immunothrombosis; (IV) the inflammatory cascade induced by SARS-CoV-2 often leads to hypercoagulability and promotes the formation and progress of atherosclerosis; (V) antiphospholipid antibodies are also detected in plasma of some severe cases, which aggravate the thrombosis through the formation of immune complexes; (VI) hyperglycemia in COVID-19 patients may trigger CVD by increasing oxidative stress and blood viscosity; (VII) the COVID-19 outbreak is a global emergency and causes psychological stress, which could be a potential risk factor of CVD as coagulation, and fibrinolysis may be affected. In this review, we aimed to further our understanding of CVD-associated COVID-19 infection, which could improve the therapeutic outcomes of patients. Personalized treatments should be offered to COVID-19 patients at greater risk for stroke in future clinical practice.

Background: The Coronavirus Disease 2019 (COVID-19) is becoming the major health issue in recent human history with thousands of deaths and millions of cases worldwide. Newer research and old experience with other coronaviruses highlighted a probable underlying mechanism of disturbance of the renin-angiotensin system (RAS) that is associated with the intrinsic effects of SARS-CoV-2 infection., Objective: In this review, we aimed to describe the intimate connections between the RAS components, the immune system and COVID-19 pathophysiology., Methods: This non-systematic review article summarizes recent evidence on the relationship between COVID-19 and the RAS., Results: Several studies have indicated that the downregulation of membrane-bound ACE2 may exert a key role for the impairment of immune functions and for COVID-19 patients' outcomes. The downregulation may occur by distinct mechanisms, particularly: (1) the shedding process induced by the SARS-CoV-2 fusion pathway, which reduces the amount of membrane-bound ACE2, stimulating more shedding by the high levels of Angiotensin II; (2) the endocytosis of ACE2 receptor with the virus itself and (3) by the interferon inhibition caused by SARS-CoV-2 effects on the immune system, which leads to a reduction of ACE2 receptor expression., Conclusion: Recent research provides evidence of a reduction of the components of the alternative RAS axis, including ACE2 and Angiotensin-(1-7). In contrast, increased levels of Angiotensin II can activate the AT1 receptor in several organs. Consequently, increased inflammation, thrombosis and angiogenesis occur in patients infected with SARS-COV-2. Attention should be paid to the interactions of the RAS and COVID-19, mainly in the context of novel vaccines and proposed medications., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Biological sex is increasingly recognized as a critical determinant of health and disease, particularly relevant to the topical COVID-19 pandemic caused by the SARS-CoV-2 coronavirus. Epidemiological data and observational reports from both the original SARS epidemic and the most recent COVID-19 pandemic have a common feature: males are more likely to exhibit enhanced disease severity and mortality than females. Sex differences in cardiovascular disease and COVID-19 share mechanistic foundations, namely, the involvement of both the innate immune system and the canonical renin-angiotensin system (RAS). Immunological differences suggest that females mount a rapid and aggressive innate immune response, and the attenuated antiviral response in males may confer enhanced susceptibility to severe disease. Furthermore, the angiotensin-converting enzyme 2 (ACE2) is involved in disease pathogenesis in cardiovascular disease and COVID-19, either to serve as a protective mechanism by deactivating the RAS or as the receptor for viral entry, respectively. Loss of membrane ACE2 and a corresponding increase in plasma ACE2 are associated with worsened cardiovascular disease outcomes, a mechanism attributed to a disintegrin and metalloproteinase (ADAM17). SARS-CoV-2 infection also leads to ADAM17 activation, a positive feedback cycle that exacerbates ACE2 loss. Therefore, the relationship between cardiovascular disease and COVID-19 is critically dependent on the loss of membrane ACE2 by ADAM17-mediated proteolytic cleavage. This article explores potential mechanisms involved in COVID-19 that may contribute to sex-specific susceptibility focusing on the innate immune system and the RAS, namely, genetics and sex hormones. Finally, we highlight here the added challenges of gender in the COVID-19 pandemic.

There is a striking age-related disparity in the prevalence and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced coronavirus disease 2019 infections, which might be explained by age-dependent immunological mechanisms. These include age-related physiological differences in immunological responses, cross-neutralizing antibodies, and differences in levels and binding affinity of angiotensin-converting enzyme 2, the SARS-CoV-2 target receptor; antibody-dependent enhancement in adults manifesting with an overexuberant systemic inflammation in response to infection; and the increased likelihood of comorbidities in adults and the elderly. Emerging immunological phenomena such as Pediatric Multi-System Inflammatory Disorder Temporally associated with SARS-CoV-2 or Multisystem Inflammatory Syndrome in Children are now being observed, though the underlying mechanisms are still unclear. Understanding the mechanisms through which pediatric patients are protected from severe novel coronaviruses infections will provide critical clues to the pathophysiology of coronavirus disease 2019 infection and inform future therapeutic and prophylactic interventions. Asymptomatic carriage in children may have major public health implications, which will have an impact on social and health care policies on screening and isolation practices, school reopening, and safe distancing requirements in the community., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Patients with COVID-19 who require ICU admission might have the cytokine storm. It is a state of out-of-control release of a variety of inflammatory cytokines. The molecular mechanism of the cytokine storm has not been explored extensively yet. The attachment of SARS-CoV-2 spike glycoprotein with angiotensin-converting enzyme 2 (ACE2), as its cellular receptor, triggers complex molecular events that leads to hyperinflammation. Four molecular axes that may be involved in SARS-CoV-2 driven inflammatory cytokine overproduction are addressed in this work. The virus-mediated down-regulation of ACE2 causes a burst of inflammatory cytokine release through dysregulation of the renin-angiotensin-aldosterone system (ACE/angiotensin II/AT1R axis), attenuation of Mas receptor (ACE2/MasR axis), increased activation of [des-Arg9]-bradykinin (ACE2/bradykinin B1R/DABK axis), and activation of the complement system including C5a and C5b-9 components. The molecular clarification of these axes will elucidate an array of therapeutic strategies to confront the cytokine storm in order to prevent and treat COVID-19 associated acute respiratory distress syndrome., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: An award was given to Iraj Nabipour by “Novo Nordisk Pars” (The Best Innovator of Diabetes in Iran 2013). For the remaining authors none were declared., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

To date the pathophysiology of COVID-19 remains unclear: this represents a factor determining the current lack of effective treatments. In this paper, we hypothesized a complex host response to SARS-CoV-2, with the Contact System (CS) playing a pivotal role in innate immune response. CS is linked with different proteolytic defense systems operating in human vasculature: the Kallikrein-Kinin (KKS), the Coagulation/Fibrinolysis and the Renin-Angiotensin (RAS) Systems. We investigated the role of the mediators involved. CS consists of Factor XII (FXII) and plasma prekallikrein (complexed to high-molecular-weight kininogen-HK). Autoactivation of FXII by contact with SARS-CoV-2 could lead to activation of intrinsic coagulation, with fibrin formation (microthrombosis), and fibrinolysis, resulting in increased D-dimer levels. Activation of kallikrein by activated FXII leads to production of bradykinin (BK) from HK. BK binds to B2-receptors, mediating vascular permeability, vasodilation and edema. B1-receptors, binding the metabolite [des-Arg 9 ]-BK (DABK), are up-regulated during infections and mediate lung inflammatory responses. BK could play a relevant role in COVID-19 as already described for other viral models. Angiotensin-Converting-Enzyme (ACE) 2 displays lung protective effects: it inactivates DABK and converts Angiotensin II (Ang II) into Angiotensin-(1-7) and Angiotensin I into Angiotensin-(1-9). SARS-CoV-2 binds to ACE2 for cell entry, downregulating it: an impaired DABK inactivation could lead to an enhanced activity of B1-receptors, and the accumulation of Ang II, through a negative feedback loop, may result in decreased ACE activity, with consequent increase of BK. Therapies targeting the CS, the KKS and action of BK could be effective for the treatment of COVID-19., (Copyright © 2020 Meini, Zanichelli, Sbrojavacca, Iuri, Roberts, Suffritti and Tascini.)

Early clinical evidence suggests that severe cases of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are frequently characterized by hyperinflammation, imbalance of renin-angiotensin-aldosterone system, and a particular form of vasculopathy, thrombotic microangiopathy, and intravascular coagulopathy. In this paper, we present an immunothrombosis model of COVID-19. We discuss the underlying pathogenesis and the interaction between multiple systems, resulting in propagation of immunothrombosis, which through investigation in the coming weeks, may lead to both an improved understanding of COVID-19 pathophysiology and identification of innovative and efficient therapeutic targets to reverse the otherwise unfavorable clinical outcome of many of these patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

We believe that, in parallel to the attempts for direct blockade of the SARS-CoV-2 penetration into host cell and repurposing drugs, finding new therapeutic strategies for patients with lung injury or cardiovascular complications/coagulopathies associated with COVID-19 should be paid particular attention. Apelin or its receptor agonists are of great potential treatment for COVID-19 through suppressing angiotensin-converting enzyme (ACE) and angiotensin II (Ang-II) production, as well as, down-regulating angiotensin receptor 1 (AT1R) and ACE2 up-regulation. These drugs have potential to improve acute lung injury and cardiovascular/coagulopathy complications in COVID-19 which are associated with elevated Ang-II/Ang(1-7) ratio., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Patients with Systemic Lupus Erythematosus (SLE) suffer from a chronic inflammatory autoimmune disease that results from the body's immune system targeting healthy tissues which causes damage to various organ systems. Patients with lupus are still in need of effective therapies to treat this complex, multi-system disease. Because polymorphisms in ACE are associated with the activity of SLE and lupus nephritis and based on well-documented renal-protective effects of Renin Angiotensin System (RAS)-modifying therapies, ACE-I are now widely used in patients with SLE with significant efficacy. Our research explores alternate ways of modifying the RAS as a potential for systemic therapeutic benefit in the MRL -lpr mouse model of SLE. These therapeutics include; angiotensin (1-7) [A(1-7)], Nor-Leu-3 Angiotensin (1-7) (NorLeu), Losartan (ARB), and Lisinopril (ACE-I). Daily systemic treatment with all of these RAS-modifying therapies significantly reduced the onset and intensity in rash formation and swelling of the paw. Further, histology showed a corresponding decrease in hyperkeratosis and acanthosis in skin sections. Important immunological parameters such as decreased circulating anti-dsDNA antibodies, lymph node size, and T cell activation were observed. As expected, the development of glomerular pathologies was also attenuated by RAS-modifying therapy. Improved number and health of mesenchymal stem cells (MSCs), as well as reduction in oxidative stress and inflammation may be contributing to the reduction in SLE pathologies. Several studies have already characterized the protective role of ACE-I and ARBs in mouse models of SLE, here we focus on the protective arm of RAS. A(1-7) in particular demonstrates several protective effects that go beyond those seen with ACE-Is and ARBs; an important finding considering that ACE-Is and ARBs are teratogenic and can cause hypotension in this population. These results offer a foundation for further pharmaceutical development of RAS-modifying therapies, that target the protective arm, as novel SLE therapeutics that do not rely on suppressing the immune system., (Copyright © 2020 Soto, Delatorre, Hurst and Rodgers.)

Investigations reported that hypertension, diabetes, and cardiovascular diseases were the most prevalent comorbidities among the patients with coronavirus disease 2019 (COVID-19). Hypertension appeared consistently as the most prevalent risk factors in COVID-19 patients. Some investigations speculated about the association between renin-angiotensin-aldosterone system (RAAS) and susceptibility to COVID-19, as well as the relationship between RAAS inhibitors and increased mortality in these patients. This raised concern about the potential association between hypertension (and its treatment) and propensity for COVID-19. There are only a few follow-up studies that investigated the impact of comorbidities on outcome in these patients with conflicting findings. Hypertension has been proven to be more prevalent in patients with an adverse outcome (admission in intensive care unit, use of mechanical ventilation, or death). So far, there is no study that demonstrated independent predictive value of hypertension on mortality in COVID-19 patients. There are many speculations about this coronavirus and its relation with different risk factors and underlying diseases. The aim of this review was to summarize the current knowledge about the relationship between hypertension and COVID-19 and the role of hypertension on outcome in these patients., (© 2020 Wiley Periodicals LLC.)

Severe acute respiratory syndrome coronavirus 2 has spread rapidly around the globe. However, despite its high pathogenicity and transmissibility, the severity of the associated disease, COVID-19, varies widely. While the prognosis is favorable in most patients, critical illness, manifested by respiratory distress, thromboembolism, shock, and multi-organ failure, has been reported in about 5% of cases. Several studies have associated poor COVID-19 outcomes with the exhaustion of natural killer cells and cytotoxic T cells, lymphopenia, and elevated serum levels of D-dimer. In this article, we propose a common pathophysiological denominator for these negative prognostic markers, endogenous, angiotensin II toxicity. We hypothesize that, like in avian influenza, the outlook of COVID-19 is negatively correlated with the intracellular accumulation of angiotensin II promoted by the viral blockade of its degrading enzyme receptors. In this model, upregulated angiotensin II causes premature vascular senescence, leading to dysfunctional coagulation, and immunity. We further hypothesize that angiotensin II blockers and immune checkpoint inhibitors may be salutary for COVID-19 patients with critical illness by reversing both the clotting and immune defects (Graphical Abstract)., (Copyright © 2020 Sfera, Osorio, Jafri, Diaz and Campo Maldonado.)

IL (Interleukin)-1 antagonism decreases blood pressure in obese individuals. The underlying mechanisms are unknown. Based on experimental data, we hypothesized an effect of IL-1 antagonism via modulation of the renin-angiotensin-aldosterone system. In this explorative study, we examined shorter- (2 days) and longer-term effects (4 weeks) of IL-1 antagonism (anakinra/Kineret) on renin-angiotensin system peptide profiles and on hemodynamic parameters assessed by noninvasive measurement in obese (body mass index ≥30 kg/m 2 ) individuals from 2 interventional trials (a prospective interventional trial [n=73] and a placebo controlled-double blinded interventional trial [n=67]). A total of 140 patients were included. Systolic blood pressure decreased after short-term (absolute difference -5.2 mm Hg [95% CI, -8.5 to -1.8]; P =0.0006) and after longer-term treatment with anakinra (absolute difference -3.9 mm Hg [95% CI, -7.59 to -0.21]; P =0.04), with no change in blood pressure in the placebo group. Upon IL-1 antagonism, equilibrium levels of Ang II (angiotensin II), Ang I, aldosterone, and renin remained unchanged. In contrast, Ang (1-7) peptide levels increased after 4 weeks (between-group difference 16.35 pmol/L [95% CI, 1.22-30.17], P =0.03), as well as the Ang (1-7)/Ang II ratio (between-group difference 0.42 [95% CI, 0.17-0.67], P =0.02) in comparison to placebo. Consistently, the stroke systemic vascular resistance index significantly decreased in the anakinra group (between-group difference of -62.65 dyn/sec per cm -5 per m 2 [95% CI, -116.94 to -18.36], P =0.008, consistent with a 25% decrease). IL-1 antagonism increased the vasodilatory Ang (1-7) peptide after 4 weeks of treatment in obese individuals, paralleled by a decrease in peripheral vascular resistance. These findings point to an IL-1 mediated blood pressure-lowering mechanism via modulation of Ang (1-7). Registration- URL: https://www.clinicaltrials.gov. Unique identifiers: NCT02227420 and NCT02672592.

Background: It is now recognized that many anticancer treatments positively modulate the antitumor immune response. Clinical and experimental studies have shown that inhibitors of the classical renin-angiotensin system (RAS) reduce tumor progression and are associated with better outcomes in patients with colorectal cancer. RAS components are expressed by most immune cells and adult hematopoietic cells, thus are potential targets for modulating tumor-infiltrating immune cells and can provide a mechanism of tumor control by the renin-angiotensin system inhibitors (RASi)., Aim: To investigate the effects of the RASi captopril on tumor T lymphocyte distribution in a mouse model of colorectal liver metastases., Methods: Liver metastases were established in a mouse model using an autologous colorectal cancer cell line. RASi (captopril 750 mg/kg) or carrier (saline) was administered to the mice daily via intraperitoneal injection, from day 1 post-tumor induction to endpoint (day 15 or 21 post-tumor induction). At the endpoint, tumor growth was determined, and lymphocyte infiltration and composition in the tumor and liver tissues were analyzed by flow cytometry and immunohistochemistry (IHC)., Results: Captopril significantly decreased tumor viability and impaired metastatic growth. Analysis of infiltrating T cells into liver parenchyma and tumor tissues by IHC and flow cytometry showed that captopril significantly increased the infiltration of CD3 + T cells into both tissues at day 15 following tumor induction. Phenotypical analysis of CD45 + CD3 + T cells indicated that the major contributing phenotype to this influx is a CD4 and CD8 double-negative T cell (DNT) subtype, while CD4 + T cells decreased and CD8 + T cells remained unchanged. Captopril treatment also increased the expression of checkpoint receptor PD-1 on CD8 + and DNT subsets ., Conclusion: Captopril treatment modulates the immune response by increasing the infiltration and altering the phenotypical composition of T lymphocytes and may be a contributing mechanism for tumor control., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Diabetic nephropathy (DN) is one of the most serious chronic kidney diseases and the major cause of end-stage renal failure worldwide. The underlying mechanisms of DN are complex and required to be further investigated. Both innate immunity and renin-angiotensin system (RAS) play critical roles in the pathogenesis of DN. Except for traditional functions, abnormally regulated RAS has been proved to be involved in the inflammatory process of DN. Toll-like receptor 4 (TLR4) is the most deeply studied pattern recognition receptor in the innate immune system, and its activation has been reported to mediate the development of DN. In this review, we aim at discussing how dysregulated RAS affects TLR4 activation in the kidney that contributes to the exploration of the pathogenesis of DN. Understanding the interplay of RAS and TLR4 in inducing the progression of DN may provide new insights to develop effective treatments., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Qi Feng et al.)

Inflammation and gut dysbiosis are hallmarks of hypertension (HTN). Hydrogen sulfide (H 2 S) is an important freely diffusing molecule that modulates the function of neural, cardiovascular and immune systems, and circulating levels of H 2 S are reduced in animals and humans with HTN. While most research to date has focused on H₂S produced endogenously by the host, H 2 S is also produced by the gut bacteria and may affect the host homeostasis. Here, we review an association between neuroinflammation and gut dysbiosis in HTN, with special emphasis on a potential role of H 2 S in this interplay., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Patients with Type 2 Diabetes Mellitus (T2DM) suffer from a higher incidence and severity of pulmonary infections. This is likely due to immune impairment and structural abnormalities caused by T2DM-induced oxidative stress (OS) and chronic inflammation. Modulation of the Renin Angiotensin System (RAS) through blockade of the actions of angiotensin II (AII), or inducing the protective pathway, has the potential to reduce these pathological pathways. The effects of Angiotensin 1-7 [A(1-7)] and NorLeu 3 -A(1-7) [NorLeu], ligands of the protective RAS, on the innate immune response were evaluated in the db/db mouse model of T2DM. Only NorLeu treatment reduced the structural pathologies in the lung caused by T2DM. A decreased in bactericidal activity and phagocytosis in diabetic animals was also observed; both A(1-7) and NorLeu treatment restored these functions. Myeloid progenitor CFUs were reduced and neutrophil/progenitor OS was increased in saline-treated db/db mice, and was reversed by A(1-7) and NorLeu treatment. These results demonstrate the adverse effects of diabetes on factors that contribute to pulmonary infections and the therapeutic potential of protective RAS peptides. Overall, RAS-modification may be a viable therapeutic target to treat diabetic complications that are not addressed by glucose lowering drugs., (Copyright © 2019 Soto, Gaffney and Rodgers.)

Aim: Renin-angiotensin system (RAS) is thought to have a noticeable effect in the pathophysiological injury in multiple organs by inducing different cellular and molecular reactions. The objective of the current study is to investigate the possible protective effects of perindopril against lipopolysaccharide (LPS)-induced cardiopulmonary oxidative and inflammatory damage in rats. Methods: To achieve this goal, animals were randomly divided into six groups: normal group, LPS group (3 mg/kg, i.p., single dose), perindopril-LPS treated group (1 mg/kg/day, i.p.), perindopril-LPS treated group (2 mg/kg/day, i.p.), and two perindopril negative groups (perindopril 1 or 2 mg/kg/day, i.p.) alone for seven days. Lungs and hearts tissue angiotensin II (Ang-II), angiotensin-1-7 (Ang-1-7), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were assessed using ELISA. Nuclear factor kappa-B-p65 (NF-κB-p65) was assessed using real time PCR, while protein kinase B (Akt) was evaluated by Western blot analysis. Furthermore, oxidative stress biomarkers and myeloperoxidase (MPO) enzyme were evaluated spectrophotometrically. Tissues inducible and endothelial nitric oxide synthases (iNOS and eNOS) were assessed immunohistochemically. Histopathological study was carried out to confirm our results. Results: LPS-intoxicated rats significantly elevated Ang-II, NF-κB-p65, Akt, and iNOS levels, coupled with significant down-regulation of Ang-1-7 and eNOS levels and corrected the oxidative stress biomarkers. Perindopril administration significantly attenuated the disturbances induced by LPS in a dose-dependent manner. Conclusion: Perindopril mitigates LPS-induced heart and lung damage through modulation of RAS, iNOS/eNOS, Akt, and NF-κB-p65 signaling pathways.

Background and Purpose: Both innate immunity and the renin-angiotensin system (RAS) play important roles in the pathogenesis of diabetic nephropathy (DN). Myeloid differentiation factor 2 (MD2) is a co-receptor of toll-like receptor 4 (TLR4) in innate immunity. While TLR4 is involved in the development of DN, the role of MD2 in DN has not been characterized. It also remains unclear whether the MD2/TLR4 signalling pathway is associated with RAS activation in diabetes., Experimental Approach: MD2 was blocked using siRNA or the low MW inhibitor, L6H9, in renal proximal tubular cells (NRK-52E cells) exposed to high concentrations of glucose (HG). In vivo, C57BL/6 and MD2 -/- mice were injected with streptozotocin to induce Type 1 diabetes and nephropathy., Key Results: Inhibition of MD2 by genetic knockdown or the inhibitor L6H9 suppressed HG-induced expression of ACE and angiotensin receptors and production of angiotensin II in NRK-52E cells, along with decreased fibrosis markers (TGF-β and collagen IV). Inhibition of the MD2/TLR4-MAPKs pathway did not affect HG-induced renin overproduction. In vivo, using the streptozotocin-induced diabetic mice, MD2 was overexpressed in diabetic kidney. MD2 gene knockout or L6H9 attenuated renal fibrosis and dysfunction by suppressing local RAS activation and inflammation., Conclusions and Implications: Hyperglycaemia activated the MD2/TLR4-MAPKs signalling cascade to induce renal RAS activation, leading to renal fibrosis and dysfunction. Pharmacological inhibition of MD2 may be considered as a therapeutic approach to mitigate DN and the low MW inhibitor L6H9 could be a candidate for such therapy., (© 2019 The British Pharmacological Society.)

A growing body of literature has elucidated the involvement of the central renin-angiotensin system (RAS) in various neuropsychiatric diseases. While consensus on the exact mechanism of the central RAS in schizophrenia pathophysiology does not currently exist, increasing evidence reveals promise in harnessing the therapeutic potential of RAS modulation in the treatment of schizophrenia. In this review, we examine how the central RAS affects inflammation, glutamate, dopamine, gamma-aminobutyric acid (GABA), and peroxisome proliferator-activated receptor (PPAR)-γ, all of which are associated with schizophrenia etiology. In addition, a recent study has demonstrated the therapeutic potential of RAS modulators, especially angiotensin II type 1 receptor blockers (ARBs), as adjunctive therapy to the currently available antipsychotic medications for schizophrenia treatment. With a greater understanding of how RAS inhibition directly modulates neurotransmitter balance in the brain, it is possible that compounds with RAS-inhibiting properties could be used to optimize physiological levels of glutamate, dopamine, and GABA, and the balance among the three neurotransmitters, analogously to how antipsychotic medications mediate the dopaminergic pathways. It can be hoped that a novel approach based on this concept, such as adjunctive telmisartan therapy, may offer practical interventional strategies to address currently unmet therapeutic needs in patients with schizophrenia, especially those with treatment-resistant schizophrenia.

Cardiovascular disease and infections are directly or indirectly associated with an altered immune response, which leads to a high incidence of morbidity and mortality, and together, they account for up to 70% of all deaths among patients with chronic kidney dysfunction. Impairment of the normal reaction of the innate and adaptive immune systems in chronic kidney disease predisposes patients to an increased risk of infections, virus-associated cancers, and a diminished vaccine response. On the other hand, an abnormal, exaggerated reaction of the immune systems can also occur in this group of patients, resulting in increased production and decreased clearance of proinflammatory cytokines, which can lead to inflammation and its sequelae (eg, atherosclerotic cardiovascular disease). Epigenetically, modifications in hematopoietic stem cells involving a shift from lymphoid to myeloid cell lineage may underlie uremia-associated immunological senescence, which is not reversed by renal replacement therapy, including kidney transplantation. Measures aimed at attenuating the immune abnormalities in chronic kidney disease/end-stage renal disease should be an area of focused research as this could potentially lead to a better understanding and, thus, development of therapies that could reduce the disastrously high death rate in this patient population. The aim of the present article is to review the characteristics, causes, and mechanisms of the immune dysfunction related to chronic kidney disease., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Women are at increased risk for developing depression and cardiovascular disease (CVD) across the lifespan and their comorbidity is associated with adverse outcomes that contribute significantly to rates of morbidity and mortality in women worldwide. Immune-system activity has been implicated in the etiology of both depression and CVD, but it is unclear how inflammation contributes to sex differences in this comorbidity. This narrative review provides an updated synthesis of research examining the association of inflammation with depression and CVD, and their comorbidity in women. Recent research provides evidence of pro-inflammatory states and sex differences associated with alterations in the hypothalamic-pituitary-adrenal axis, the renin-angiotensin-aldosterone system and the serotonin/kynurenine pathway, that likely contribute to the development of depression and CVD. Changes to inflammatory cytokines in relation to reproductive periods of hormonal fluctuation (i.e. the menstrual cycle, perinatal period and menopause) are highlighted and provide a greater understanding of the unique vulnerability women experience in developing both depressed mood and adverse cardiovascular events. Inflammatory biomarkers hold substantial promise when combined with a patient's reproductive and mental health history to aid in the prediction, identification and treatment of the women most at risk for CVD and depression. However, more research is needed to improve our understanding of the mechanisms underlying inflammation in relation to their comorbidity, and how these findings can be translated to improve women's health.

Purpose of Review: Mechanisms facilitating progression of hypertension via cross stimulation of the renin-angiotensin system (RAS) and inflammation have been proposed. Accordingly, we review and update evidence for regulation of RAS components by pro-inflammatory factors., Recent Findings: Angiotensin II (Ang II), which is produced by RAS, induces vasoconstriction and consequent blood pressure elevation. In addition to this direct action, chronically elevated Ang II stimulates several pathophysiological mechanisms including generation of oxidative stress, stimulation of the nervous system, alterations in renal hemodynamics, and activation of the immune system. In particular, an activated immune system has been shown to contribute to the development of hypertension. Recent studies have demonstrated that immune cell-derived pro-inflammatory cytokines regulate RAS components, further accelerating systemic and local Ang II formation. Specifically, regulation of angiotensinogen (AGT) production by pro-inflammatory cytokines in the liver and kidney is proposed as a key mechanism underlying the progression of Ang II-dependent hypertension.

Chronic obstructive pulmonary disease (COPD) is a complex disorder that primarily affects the lungs and is characterized not only by local pulmonary, but also by systemic inflammation which promotes the development of extrapulmonary and cardiovascular co-morbidities. Angiotensin converting enzyme (ACE) inhibitors and ARBs (angiotensin receptor blockers) are widely used drugs in the treatment of cardiovascular diseases, with growing evidence suggesting potential benefits in COPD patients. The purpose of this review is to describe the correlation of renin-angiotensin system (RAS) with COPD pathophysiology and to present the latest data regarding the potential role of RAS blockers in COPD.

Background: The renin-angiotensin system (RAS) is an important enzymatic system responsible for the regulation of biological functions, such as the arterial pressure, hydroelectrolytic control, vascular vasodilatation/vasoconstriction and more recently metabolic functions., Objectives: The aim of the present review is to discuss the associations between the gut microbiome and the renin-angiotensin system and the influence of their intimate relationship on the cardiovascular health., Methods: A literature review of the main studies published regarding the relationship among the renin-angiotensin system, gut microbiota and cardiovascular health was performed., Results: The association between the ACE2 and gut microbiota has been discussed. It is shown that the ACE2/Ang 1-7 axis modulates the immune response, influencing the microbiota composition, and thus being one of the causes for some diseases physiophatologies, such as diarrhea and intestinal inflammatory disease., Conclusion: The association between RAS and gut microbiota seems to have a strong influence on the genesis of cardiovascular diseases, through direct mechanisms, such as nerve stimulation, or indirectly on metabolic parameters, such as weight, adiposity and lipid profile., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Drugs interfering with the renin-angiotensin-aldosterone system (RAAS) improved the prognosis in patients with hypertension, heart failure, diabetes and chronic kidney disease. However, combining different drugs brought no further benefit while increasing the risk of hyperkalemia, hypotension and acute renal failure. This was so with combining angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptors type 1 antagonists (ARB). Dissimilarly, in animal disease models this dual therapy proved clearly superior to single drug treatment and became the optimal standard regime for comparison with other treatments. This review analyzes the causes of the discrepancy of effects of the dual therapy between animal experiments versus clinical studies, and is focused on the outcomes in chronic kidney disease. Discussed is the role of species differences in RAAS, of the variability of the disease features in humans versus relative stability in animals, of the genetic uniformity in the animals but not in humans, and of the biased publication habits of experimental versus clinical studies. We attempt to understand the causes and reconcile the discordant findings and suggest to what extent dual RAAS inhibition should be continued in animal experiments and why its application in the clinics should be limited to strictly selected groups of patients.

Background and Purpose: Medication nonadherence is one of major risk factors for the poor outcome in ischemic stroke. Vaccination is expected to solve such a problem because of its long-lasting effects, but its effect on ischemic brain damage is still unknown. Here, we focused on vaccination for renin-angiotensin system and examined the effects of angiotensin II (Ang II) peptide vaccine in permanent middle cerebral artery occlusion model in rats., Methods: Male Wistar rats were exposed to permanent middle cerebral artery occlusion after 3× injections of Ang II peptide vaccine, and the serum or brain level of anti-Ang II antibody was examined. The effects of the vaccine were evaluated by differences in infarction volume, brain renin-angiotensin system components, and markers for neurodegeneration and oxidative stress., Results: Ang II vaccination successfully produced anti-Ang II antibodies in serum without concomitant change in blood pressure. Sufficient production of serum anti-Ang II antibody led to reduction of infarct volume and induced the penetration of anti-Ang II antibody in ischemic hemisphere, with suppressed expression of Ang II type 1 receptor mRNA. Vaccinated rats with sufficient antibody production showed the reduction of Fluoro-Jade B-positive cells, spectrin fragmentation, 4-hydroxynonenal-positive cells, and Nox 2 mRNA expression., Conclusions: Our findings indicate that Ang II vaccination exerts neuroprotective and antioxidative effects in cerebral ischemia, with renin-angiotensin system blockade by penetration of anti-Ang II antibodies into ischemic brain lesion. Ang II peptide vaccination could be a promising approach to treat ischemic stroke., (© 2017 American Heart Association, Inc.)

Renin-angiotensin system (RAS) plays an important role of regulating inflammatory injury. However, it is not clear about the correlation between renin-angiotensin system (RAS) and inflammation induced by LPS in mammary gland cells. So immunofluorescence was performed to verify the ACE2 expression in mammary gland cells. MTT assay was performed to detect cell viability. ELISA was performed to detect cytokines in cell supernatant. Western Blot was performed to analyze RAS levels and ACE2 level change was observed by immunofluorescence. The TLR4 level and p65 phosphorylation were detected by Western Blot. The ACE2 protein intensively located on the cell membrane. According to the results of MTT assay and TNF-α level, the injury was evidently induced by high concentration LPS after 9h. The TNF-α, IL-6, IL-8, ACE, AT1R and AngII had an increasing expression with the rise of cell injury. In contrast, the MasR, Ang1-7 and ACE2 had a declining expression with the increase of cell injury degree. The TLR4 level and p65 phosphorylation in high concentration LPS group was significantly higher than that of control group. These results suggest that a valid inflammatory injury was induced after the cells were treated by high concentration of LPS for 9h. Meanwhile, the ACE/AngII/AT1R axis was activated and the ACE2/Ang1-7/MasR axis was depressed., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Inappropriate activation of the renin-angiotensin system (RAS) exacerbates renal and vascular injury. Accordingly, treatment with global RAS antagonists attenuates cardiovascular risk and slows the progression of proteinuric kidney disease. By reducing BP, RAS inhibitors limit secondary immune activation responding to hemodynamic injury in the target organ. However, RAS activation in hematopoietic cells has immunologic effects that diverge from those of RAS stimulation in the kidney and vasculature. In preclinical studies, activating type 1 angiotensin (AT 1 ) receptors in T lymphocytes and myeloid cells blunts the polarization of these cells toward proinflammatory phenotypes, protecting the kidney from hypertensive injury and fibrosis. These endogenous functions of immune AT 1 receptors temper the pathogenic actions of renal and vascular AT 1 receptors during hypertension. By counteracting the effects of AT 1 receptor stimulation in the target organ, exogenous administration of AT 2 receptor agonists or angiotensin 1-7 analogs may similarly limit inflammatory injury to the heart and kidney. Moreover, although angiotensin II is the classic effector molecule of the RAS, several RAS enzymes affect immune homeostasis independently of canonic angiotensin II generation. Thus, as reviewed here, multiple components of the RAS signaling cascade influence inflammatory cell phenotype and function with unpredictable and context-specific effects on innate and adaptive immunity., (Copyright © 2017 by the American Society of Nephrology.)

Membranous nephropathy is a major cause of nephrotic syndrome in adults, with various etiologies and outcomes. One third of patients enter spontaneous remission with blockade of the renin-angiotensin system, one third develop a persistent nephrotic syndrome, while another third of patients develop end-stage kidney disease and 40% of them relapse after kidney transplantation. Treatment of membranous nephropathy remains controversial. Immunosuppressive therapy is only recommended in case of renal function deterioration or persistent nephrotic syndrome after 6months of renin-angiotensin system blockade. Therefore, delayed immunosuppressive treatments may lead to significant and potentially irreversible complications. For long, no biological markers could predict clinical outcome and guide therapy. The discovery of autoantibodies to the phospholipase A2 receptor (PLA2R1) in 2009, and to the thrombospondin type 1 domain containing 7A (THSD7A) in 2014 in respectively 70 and 5% of patients with membranous nephropathy were major breakthroughs. The passive infusion of human anti-THSD7A antibodies in mouse induces proteinuria and membranous nephropathy. The identification of these antigens has allowed developing diagnostic and prognostic tests. High anti-PLA2R1 titers at time of diagnosis predict a poor renal outcome. Anti-PLA2R1 antibodies can bind at least three different domains of PLA2R1. Epitope spreading with binding of two or three of these antigenic domains is associated with active membranous nephropathy and poor renal survival. These new tools could help us to monitor disease severity and to predict renal prognosis for a better selection of patients that should benefit of early immunosuppressive therapy., (Copyright © 2017 Société francophone de néphrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.)

Background: Blockade of the renin-angiotensin system (RAS) has been shown to alleviate inflammatory processes in the gastrointestinal tract. The aim of this study was to determine if blockade of the RAS would be effective in an immunologically relevant colitis model, and to compare outcome with an acute colitis model., Methods: A losartan analog, CCG-203025 (C 23 H 26 ClN 3 O 5 S) containing a highly polar sulfonic acid moiety that we expected would allow localized mucosal antagonism with minimal systemic absorption was selected as an angiotensin II type 1a receptor antagonist (AT1aR-A). Two colitis models were studied: (1) Acute colitis was induced in 8- to 10-week-old C57BL/6J mice by 2.5 % dextran sodium sulfate (DSS, in drinking water) for 7 days. (2) IL10-/-colitis Piroxicam (200 ppm) was administered orally in feed to 5-week-old IL-10-/-mice (C57BL/6J background) for 14 days followed by enalaprilat (ACE-I), CCG-203025 or PBS administered transanally for 14 days., Results: In the DSS model, weight loss and histologic score for CCG-203025 were better than with placebo. In the IL10-/-model, ACE-I suppressed histologic damage better than CCG-203025. Both ACE-I and CCG-203025 reduced pro-inflammatory cytokines and chemokines., Conclusions: This study demonstrated the therapeutic efficacy of both ACE-I and AT1aR-A for preventing the development of both acute and immunologically relevant colitis.

Inappropriate activation of the renin angiotensin system (RAS) is a key contributor to the pathogenesis of essential hypertension. During RAS activation, infiltration of immune cells into the kidney exacerbates hypertension and renal injury. However, the mechanisms underpinning the accumulation of mononuclear cells in the kidney after RAS stimulation remain unclear. C-C motif chemokine 5 (CCL5) drives recruitment of macrophages and T lymphocytes into injured tissues, and we have found that RAS activation induces CCL5 expression in the kidney during the pathogenesis of hypertension and renal fibrosis. We therefore evaluated the contribution of CCL5 to renal damage and fibrosis in hypertensive and normotensive models of RAS stimulation. Surprisingly, during angiotensin II-induced hypertension, CCL5-deficient (knockout, KO) mice exhibited markedly augmented kidney damage, macrophage infiltration, and expression of proinflammatory macrophage cytokines compared with wild-type controls. When subjected to the normotensive unilateral ureteral obstruction model of endogenous RAS activation, CCL5 KO mice similarly developed more severe renal fibrosis and greater accumulation of macrophages in the kidney, congruent with enhanced renal expression of the macrophage chemokine CCL2. In turn, pharmacologic inhibition of CCL2 abrogated the differences between CCL5 KO and wild-type mice in kidney fibrosis and macrophage infiltration after unilateral ureteral obstruction. These data indicate that CCL5 paradoxically limits macrophage accumulation in the injured kidney during RAS activation by constraining the proinflammatory actions of CCL2., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Diabetic nephropathy (DN) is a multifactorial and polygenic disease with nodular glomerulosclerosis (NGS) pathognomonic for diabetes and hypertension. Patients with type 2 diabetes and hypertension have characteristic renin-angiotensin system (RAS) gene polymorphisms., Methods and Results: In this retrospective cohort study, we correlated the presence of NGS with renal function, angiotensin-converting enzyme (ACE) genotypes (DD, DI, and II), angiotensinogen (AGT) genotypes (MM, MT, and TT) and immunohistochemical staining characteristics of RAS components in 847 patients and 172 consecutive autopsy cases with type 2 diabetes. T allele of AGT was associated with macroalbuminuria (P = 0.040). Multitude regression analysis revealed ACE insertion (I)/deletion (D) polymorphism as an independent determinant for estimated glomerular filtration rate (eGFR) less than 60 mL min(-1)·1.73 m(-2) (DD carriers: odds ratio [OR] = 3.46, 95% confidence interval [CI] = 1.08-11.07; DI carriers: OR = 3.51, 95% CI = 1.63-7.56). A significant association between NGS and eGFR less than 60 mL min(-1)·1.73 m(-2) also persisted after adjusting for nonlinear relationship (P < 0.001). In NGS patients, immunoreactivity of angiotensin I converting enzyme 2 (ACE2) significantly decreased in glomeruli with mesangial nodules compared with glomeruli without the mesangial nodules., Conclusions: These data suggest associations of ACE D allele with glomerular filtration impairment, and NGS with glomerular ACE2 down-regulation and reduced glomerular filtration in Chinese patients with type 2 diabetes., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

ANG II is thought to increase sympathetic outflow by increasing oxidative stress and promoting local inflammation in the paraventricular nucleus (PVN) of the hypothalamus. However, the relative contributions of inflammation and oxidative stress to sympathetic drive remain poorly understood, and the underlying cellular and molecular targets have yet to be examined. ANG II has been shown to enhance Toll-like receptor (TLR)4-mediated signaling on microglia. Thus, in the present study, we aimed to determine whether ANG II-mediated activation of microglial TLR4 signaling is a key molecular target initiating local oxidative stress in the PVN. We found TLR4 and ANG II type 1 (AT1) receptor mRNA expression in hypothalamic microglia, providing molecular evidence for the potential interaction between these two receptors. In hypothalamic slices, ANG II induced microglial activation within the PVN (∼65% increase, P < 0.001), an effect that was blunted in the absence of functional TLR4. ANG II increased ROS production, as indicated by dihydroethidium fluorescence, within the PVN of rats and mice (P < 0.0001 in both cases), effects that were also dependent on the presence of functional TLR4. The microglial inhibitor minocycline attenuated ANG II-mediated ROS production, yet ANG II effects persisted in PVN single-minded 1-AT1a knockout mice, supporting the contribution of a non-neuronal source (likely microglia) to ANG II-driven ROS production in the PVN. Taken together, these results support functional interactions between AT1 receptors and TLR4 in mediating ANG II-dependent microglial activation and oxidative stress within the PVN. More broadly, our results support a functional interaction between the central renin-angiotensin system and innate immunity in the regulation of neurohumoral outflows from the PVN., (Copyright © 2016 the American Physiological Society.)

Immune cells may take part in the renin-angiotensin-aldosterone system (RAAS), which plays a pivotal role in the regulation of vascular tone and blood pressure. The aim of the study was to analyse the expression and activity of angiotensin-converting enzyme type 1 (ACE1) and ACE2 in human monocytes (MO) and their subsets. The highest relative level of ACE1-, as well as ACE2-mRNA expression, was observed in CD14(++)CD16(-) (classical) MO. Moreover, in these cells, mean level of ACE2-mRNA was almost two times higher than that of ACE1-mRNA (11.48 versus 7.073 relative units, respectively). In peripheral blood mononuclear cells (PBMC), MO and classical MO, ACE1 and ACE2 protein expression was stronger compared to other MO subpopulations. The highest level of Ang II generated from Ang I in vitro was observed in classical MO. In this setting, generation of Ang-(1-9) by PBMC and classical MO was higher when compared to the whole MO population (P < 0.05). The generation rate of vasoprotective Ang-(1-7) was comparable in all analysed cell populations. However, in CD14(+)CD16(++) (non-classical) MO, formation of Ang-(1-7) was significantly greater than Ang II (P < 0.001). We suggest that in physiological conditions MO (but also lymphocytes forming the rest of PBMC pool) may be involved in the regulation of vessel wall homeostasis via the RAAS-related mechanisms. Moreover, non-classical MO, which are associated preferentially with the vascular endothelium, express the vasoprotective phenotype., (© 2015 British Society for Immunology.)